Funds are requested to establish a Center for the investigation of unique strategies to target disease through protease inhibition. A multi-disciplinary approach involving in vitro cellular interactions, synthesis, drug design, targeting-delivery, and biopharmaceutics will be undertaken. The Center will coordinate the expertise of four faculty from Chemistry (Cook, Mallik, Rodgers, and Sibi) and two from Pharmacy (Balaz and Sehgal). The scientific focus of the Center will be the development of therapeutic inhibitors and delivery systems for matrix proteinases, including the family of matrix metalloproteinases (MMPs) and the serine proteases (SPs), urokinase plasminogen activator (uPA) and plasmin. The majority of effort is directed toward the inhibition of MMPs. However, the two serine proteases also play critical roles in matrix homeostasis in both health and disease. A portion of the effort will be directed towards the design and optimization of inhibitors for these enzymes. The effort will consist of four interrelated projects: Project 1, Synthesis; Project 2, Targeting/Delivery; Project 3, Biopharmaceutics/Drug Design; Project 4, in vitro Cellular Interactions (Core). The COBRE Center will build the infrastructure to foster growth of biomedical research in North Dakota. From July 1997 to December 1999 a total of 130 proposals from North Dakota to NIH have been submitted. As of this writing, NDSU has 15 researchers with NIH funded programs. There are on the order of 200 faculty/researchers with biomedically relevant research programs in North Dakota. The disparity between the number of researchers and grant proposal activity represents a potential growth area for the state. The investigators will develop this potential through establishment of the COBRE funded Research Center. The Center will initiate new activities in biomedically relevant areas to address the aforementioned growth areas in a holistic way. These initiatives include: seed grants for North Dakota faculty, establishment of a graduate fellowship program, post-doctoral fellowships, summer research program for undergraduates and faculty from four-year colleges, and NIH workshops. The Center will be vigilant in building and maintaining a favorable environment for fostering new proposals to the NIH at the RO1 level.